Neural prosthetic devices offer great promise for treating human disease and providing methods for the long-term study of brain neurons. One of our long-range goals is improving the function of neural prosthetic devices by controlling cellular responses around these devices. The primary focus of this proposal is the promotion of high connectivity between neurons and electrodes on prosthetic devices. Such connectivity will replace lost neurons in degenerative disease, e.g. Parkinson's disease, or control pathologic events, e.g. epilepsy, or provide necessary brain input/output following brain injury, e.g. stroke or trauma. We propose to use a multidisciplinary approach to design and fabricate devices that will allow us to test our principal hypothesis that neurotrophic factors, e.g. nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) can be used to promote neuron sprouting and direct process growth to electrode sites on prosthetic devices. Principles of chemical engineering and nanofabrication will be used to fabricate micro-machined devices coupled to slow-release polymer matrix materials or fabricated with microfluidic channels to control release of growth factors directly into neocortex. Quantitative methods will be used to describe time- and dose-dependent gradients of neurotrophins. Neuroscientists will assess neuron responses by describing and correlating morphological and electrophysiological measurements. Histochemical methods, direct neuron filling, and image analysis techniques to describe directed growth of neuron processes and their positions relative to electrode and growth factor release sites on prosthetic devices. Measurements of total electrical activity, single unit analysis, and stimulation studies will be used to describe the effects of neurotrophin treatment on connectivity between device electrodes and target neurons. Results from these experiments will provide fabrication strategies to design a new generation of functionally dynamic micro-machined prosthetic devices. These devices will provide highly conductive, long-term functional connections to neurons, insuring their use in chronic treatment and studies of the brain.